Serotonin plays a role in several psychiatric disorders, including anxiety, Alzheimer's disease, depression, nausea and vomiting, sleep, pain, eating disorders, and migraine headache. Serotonin also plays a role in both the positive and negative symptoms of schizophrenia. The central nervous system (“CNS”) distribution of serotonin and one of its receptors, the serotonin type 1B (“5HT1B”) receptor, coupled with the functional effects of serotonin suggest that 5HT1B receptor antagonists can exert important neurological and behavioral effects. In addition, 5HT1B antagonists have been shown to have antidepressant properties. Agents that selectively inhibit the 5HT1B receptor, therefore, represent a useful approach to the treatment of psychiatric disorders including major depressive disorder.
A difficulty in the development of compounds useful for the treatment of psychiatric disorders has been the lack of appropriate animal models, the limited accessibility to the brain for pharmacokinetic measurements and lack of adequate direct biomarkers relating to action on the target system. Therefore, more accurate models for performing pharmacokinetic (“PK”) and pharmacodynamic (“PD”) modeling would be achievable if central pharmacokinetic parameters such as receptor occupancy are used instead of plasma exposures.
PET is a non-invasive imaging technique that has been widely used in neuropsychopharmacological drug development. In particular, measuring the degree of receptor occupancy in the brain has been used to guide dose-selection for antidepressant and antipsychotic drugs. Additionally, PET can be used to determine the appropriate dosing regimen for a centrally acting agent by determining the rate of onset, magnitude and duration of CNS target interaction versus the plasma half-life. See, e.g., Andree B, Nyberg S, Ito H, Ginovart N, Brunner F, Jaquet F, Halldin C and Farde L. Positron emission tomographic analysis of dose-dependent MDL 100,907 binding to 5-hydroxytryptamine-2A receptors in the human brain. Journal of Clinical Psychopharmacology 18: 317-323, 1998. PET is based on the external detection and recording of the decay of positron emitters incorporated in compounds administered to in a subject. For example, molecules of biological interest (water, sugars, amino acids or synthetic compounds) have been labeled with short-lived positron emitter isotopes of biological nuclei (e.g., 11C), providing radiotracers having high specific activity and preserved biochemical properties.
Recently developed PET instruments allow one to obtain time-varying three-dimensional maps of the absolute radioactivity concentration distribution following compound  administration. By applying tracer-kinetic modeling to these PET regional time activity curves (“TACs”), it is possible to estimate absolute values of the physiological parameters that determine the interactions and fate of the radiotracer compound. PET can be used for assessing in vivo the transport and binding regional parameters of a given drug in the tissue of a mammal, or for investigating the regional effects of a drug on physiological parameters, such as blood flow, energy metabolism, or protein synthesis rate.
The utility of radioactive agents with affinity for receptors, such as serotonin receptors, for imaging tissue, either directly or indirectly, is known. For example, C.-Y. Shiue et al., Synapse, 1997, 25, 147 and S. Houle et al., Can. Nucl. Med. Commun., 1997, 18, 1130, describe the use of 5HT1A receptor ligands to image 5HT1A receptors in the human brain using PET. See also C. Halldin et al., Curr. Pharm. Design, 2001, 7(18) 1907-29.
There is a great need for CNS ligands, including 5HT1B ligands, that can be labeled with PET radionuclide and used for imaging tissue expression of this receptor system.